VCV000179429.21 - ClinVar

NM_001943.5(DSG2):c.3175T>A (p.Ser1059Thr)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(8)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Uncertain significance(2); Benign(1); Likely benign(5)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001943.5(DSG2):c.3175T>A (p.Ser1059Thr)

Variation ID: 179429 Accession: VCV000179429.21

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 18q12.1 18: 31546561 (GRCh38) [ NCBI UCSC ] 18: 29126524 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Feb 2, 2015	May 1, 2024	Nov 1, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001943.5:c.3175T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001934.2:p.Ser1059Thr	missense
NC_000018.10:g.31546561T>A
NC_000018.9:g.29126524T>A
NG_007072.3:g.53320T>A
LRG_397:g.53320T>A
LRG_397t1:c.3175T>A

... more HGVS ... less HGVS

Protein change

S1059T

Other names

Canonical SPDI

NC_000018.10:31546560:T:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00140 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00000

Trans-Omics for Precision Medicine (TOPMed) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00025

Exome Aggregation Consortium (ExAC) 0.00028

1000 Genomes Project 0.00140

1000 Genomes Project 30x 0.00141

Links

ClinGen: CA022011 dbSNP: rs201786158 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
DSG2		Some evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	1114	1921
DSG2-AS1	-	-	-	GRCh38	-	698

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not specified	Uncertain significance (1)	criteria provided, single submitter	Aug 27, 2014	RCV000156218.4
Arrhythmogenic right ventricular cardiomyopathy	Uncertain significance (1)	criteria provided, single submitter	Jun 24, 2013	RCV000171905.3
Cardiomyopathy	Benign/Likely benign (2)	criteria provided, multiple submitters, no conflicts	Jun 26, 2018	RCV000771354.4
Arrhythmogenic right ventricular dysplasia 10	Likely benign (1)	criteria provided, single submitter	Oct 26, 2023	RCV000952596.9
not provided	Likely benign (2)	criteria provided, multiple submitters, no conflicts	Nov 1, 2023	RCV001541501.4
Cardiovascular phenotype	Likely benign (1)	criteria provided, single submitter	Dec 19, 2019	RCV002321648.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Benign (Nov 28, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiomyopathy Affected status: unknown Allele origin: germline	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Accession: SCV001332956.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020
Likely benign (Oct 26, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Arrhythmogenic right ventricular dysplasia 10 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001099111.6 First in ClinVar: Dec 17, 2019 Last updated: Feb 20, 2024
Uncertain significance (Jun 24, 2013)	criteria provided, single submitter (Ng et al. (Circ Cardiovasc Genet. 2013)) Method: research	Cardiomyopathy, arrhythmogenic right ventricular Affected status: unknown Allele origin: unknown	Biesecker Lab/Clinical Genomics Section, National Institutes of Health Study: ClinSeq Accession: SCV000050907.2 First in ClinVar: Jun 04, 2015 Last updated: Sep 14, 2015 Comments (2): The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:23861362 for … (more) The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:23861362 for details. (less) Medical sequencing	Number of individuals with the variant: 1
Likely benign (Dec 31, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001759508.1 First in ClinVar: Jul 24, 2021 Last updated: Jul 24, 2021	Comment: This variant is associated with the following publications: (PMID: 17372169, 23861362)
Likely benign (Jun 26, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiomyopathy Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000903644.1 First in ClinVar: May 20, 2019 Last updated: May 20, 2019
Uncertain significance (Aug 27, 2014)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000205934.4 First in ClinVar: Feb 02, 2015 Last updated: Feb 02, 2015	Publications: PubMed (2) PubMed: 23861362‚ 17372169 Comment: The Ser1059Thr variant in DSG2 has been reported in the homozygous state in 1 Pa kistani individual with ARVD/C, though family members were not available … (more) The Ser1059Thr variant in DSG2 has been reported in the homozygous state in 1 Pa kistani individual with ARVD/C, though family members were not available for eva luation (Sen-Chowdhry 2007). This variant has also previously been identified by our laboratory in 1 Bangladeshi individual with clinical features of DCM. It ha s also been identified in 1/1740 chromosomes by the ClinSeq project (Ng 2013, db SNP rs201786158). Computational prediction tools and conservation analysis sugge st that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significan ce of the Ser1059Thr variant is uncertain. (less) Number of individuals with the variant: 2
Likely benign (Nov 01, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV004237828.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024
Likely benign (Dec 19, 2019)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002609268.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 17372169 Comment: This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more) This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)

Comment:

The Ser1059Thr variant in DSG2 has been reported in the homozygous state in 1 Pa kistani individual with ARVD/C, though family members were not available for eva luation (Sen-Chowdhry 2007). This variant has also previously been identified by our laboratory in 1 Bangladeshi individual with clinical features of DCM. It ha s also been identified in 1/1740 chromosomes by the ClinSeq project (Ng 2013, db SNP rs201786158). Computational prediction tools and conservation analysis sugge st that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significan ce of the Ser1059Thr variant is uncertain.

Comment:

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Interpreting secondary cardiac disease variants in an exome cohort.	Ng D	Circulation. Cardiovascular genetics	2013	PMID: 23861362
Clinical and genetic characterization of families with arrhythmogenic right ventricular dysplasia/cardiomyopathy provides novel insights into patterns of disease expression.	Sen-Chowdhry S	Circulation	2007	PMID: 17372169

Text-mined citations for rs201786158 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_001943.5(DSG2):c.3175T>A (p.Ser1059Thr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs201786158 ...